Association of Perceived Built Environment Attributes with Objectively Measured Physical Activity in Community-Dwelling Ambulatory Patients with Stroke.
There is little evidence on how perceptions of the built environment may influence physical activity among post-stroke patients. This study aimed to explore the associations between perceived built environment attributes and objectively measured physical activity outcomes in community-dwelling ambulatory patients with stroke. This cross-sectional study recruited patients who could walk outside without assistance. We assessed both objectively measured physical activity outcomes such as number of steps and duration of moderate-to-vigorous physical activity (MVPA) with an accelerometer and the patients' perceived surrounding built environment with the International Physical Activity Questionnaire Environmental Module. Sixty-one patients (67.0 years old) were included. The multiple linear regression analysis showed significant associations of the presence of sidewalks (β = 0.274, p = 0.016) and access to recreational facilities (β = 0.284, p = 0.010) with the number of steps taken (adjusted R2 = 0.33). In contrast, no significant associations were found between perceived built environment attributes and MVPA. These findings may help to suggest an approach to promote appropriate physical activity in patients with stroke depending on their surrounding built environment.


AKAP79/150 impacts intrinsic excitability of hippocampal neurons through phospho-regulation of A-type K+ channel trafficking.
Kv4.2, as the primary α-subunit of rapidly inactivating, A-type voltage-gated K(+) (Kv) channels expressed in hippocampal CA1 pyramidal dendrites, plays a critical role in regulating their excitability. Activity-dependent trafficking of Kv4.2 relies on C-terminal protein kinase A (PKA) phosphorylation. A-kinase-anchoring proteins (AKAPs) target PKA to glutamate receptor and ion channel complexes to allow for discrete, local signaling. As part of a previous study, we showed that AKAP79/150 interacts with Kv4.2 complexes and that the two proteins colocalize in hippocampal neurons. However, the nature and functional consequence of their interaction has not been previously explored. Here, we report that the C-terminal domain of Kv4.2 interacts with an internal region of AKAP79/150 that overlaps with its MAGUK (membrane-associated guanylate kinase)-binding domain. We show that AKAP79/150-anchored PKA activity controls Kv4.2 surface expression in heterologous cells and hippocampal neurons. Consistent with these findings, disrupting PKA anchoring led to a decrease in neuronal excitability, while preventing dephosphorylation by the phosphatase calcineurin resulted in increased excitability. These results demonstrate that AKAP79/150 provides a platform for dynamic PKA regulation of Kv4.2 expression, fundamentally impacting CA1 excitability.


Ultra-distal access of the M1 segment with the 5 Fr Navien distal access catheter in acute (anterior circulation) stroke: is it safe and efficient?
The importance of mechanical thrombectomy in acute stroke treatment has grown over recent years. Mechanical thrombectomy comprises many different techniques. Technical improvements in the catheter material have led to the development of large-bore distal access catheters which can enter tortuous intracranial vessels. This has promising applications for endovascular stroke treatment. This study evaluated the safety and success rate of ultra-distal access of the middle cerebral artery (MCA) M1 segment with the 5 Fr Navien 58 distal access catheter in the treatment of acute stroke in combination with stent retrievers. We retrospectively analyzed 81 patients with an acute stroke of the anterior circulation in whom ultra-distal access to the M1 segment was carried out using the Navien 58 catheter with an anchoring technique with a stent retriever for mechanical thrombectomy. Technical complications, success rates of catheter placement, success rates of thrombectomy using the modified Thrombolysis In Cerebral Infarction (mTICI) score, and the procedure times were evaluated. Ultra-distal access with the Navien 58 was successful in 75% (61/81) of cases. Recanalization success with a mTICI score of 2b and better was achieved in 83% overall (67/81), in 90% (55/61) of cases with successful ultra-distal access and in 60% (12/20) of cases without ultra-distal access. No severe adverse effects such as dissections or perforations occurred as a result of the ultra-distal catheter placement in the M1 segment. In 4% (3/81) of the cases a reversible MCA vasospasm occurred. Ultra-distal placement of the Navien 58 distal access catheter into the M1 segment in acute anterior circulation stroke can be achieved consistently, is safe in practice, and results in good recanalization success rates.


Comparative epigenomics in distantly related teleost species identifies conserved cis-regulatory nodes active during the vertebrate phylotypic period.
The complex relationship between ontogeny and phylogeny has been the subject of attention and controversy since von Baer's formulations in the 19th century. The classic concept that embryogenesis progresses from clade general features to species-specific characters has often been revisited. It has become accepted that embryos from a clade show maximum morphological similarity at the so-called phylotypic period (i.e., during mid-embryogenesis). According to the hourglass model, body plan conservation would depend on constrained molecular mechanisms operating at this period. More recently, comparative transcriptomic analyses have provided conclusive evidence that such molecular constraints exist. Examining cis-regulatory architecture during the phylotypic period is essential to understand the evolutionary source of body plan stability. Here we compare transcriptomes and key epigenetic marks (H3K4me3 and H3K27ac) from medaka (Oryzias latipes) and zebrafish (Danio rerio), two distantly related teleosts separated by an evolutionary distance of 115-200 Myr. We show that comparison of transcriptome profiles correlates with anatomical similarities and heterochronies observed at the phylotypic stage. Through comparative epigenomics, we uncover a pool of conserved regulatory regions (≈700), which are active during the vertebrate phylotypic period in both species. Moreover, we show that their neighboring genes encode mainly transcription factors with fundamental roles in tissue specification. We postulate that these regulatory regions, active in both teleost genomes, represent key constrained nodes of the gene networks that sustain the vertebrate body plan.


Potential of Manuka Honey as a Natural Polyelectrolyte to Develop Biomimetic Nanostructured Meshes With Antimicrobial Properties.
The use of antibiotics has been the cornerstone to prevent bacterial infections; however, the emergency of antibiotic-resistant bacteria is still an open challenge. This work aimed to develop a delivery system for treating soft tissue infections for: (1) reducing the released antimicrobial amount, preventing drug-related systemic side effects; (2) rediscovering the beneficial effects of naturally derived agents; and (3) preserving the substrate functional properties. For the first time, Manuka honey (MH) was proposed as polyelectrolyte within the layer-by-layer assembly. Biomimetic electrospun poly(ε-caprolactone) meshes were treated via layer-by-layer assembly to obtain a multilayered nanocoating, consisting of MH as polyanion and poly-(allylamine-hydrochloride) as polycation. Physicochemical characterization demonstrated the successful nanocoating formation. Different cell lines (human immortalized and primary skin fibroblasts, and primary endothelial cells) confirmed positively the membranes cytocompatibility, while bacterial tests using Gram-negative and Gram-positive bacteria demonstrated that the antimicrobial MH activity was dependent on the concentration used and strains tested.


Youth blogging and serious illness.
In recent years, a growing number of young people who experience illness tend to blog about it. In this paper, we question whether and how illness blogs illustrate the intercommunicative aspect of blogging by bringing forth both the literary concept of the implied reader and the sociological concepts of empowerment and agency in the analysis. We argue that young people blogging about serious illness demonstrate the inherent intercommunicative potential of blogging. We also argue that youth blogging about serious illness may represent a fruitful strategy for ill young people to create meaning, stay front-stage in youth communities and build self-esteem and confidence out of chaos. Furthermore, we argue that these blogs may contribute rather unique experience-based knowledge and reflections about existential issues to other young blog readers, who may otherwise not get access to this aspect of life. Youth blogging about serious illness thereby reflects a patient group so far not very visible and through the genre youth stand out as more competent when it comes to illness and healthcare issues than what is often presumed.


Further definition of antibiotic use and abuse in the surgical setting.
Surveys of the use of antimicrobial agents were conducted at three university-affiliated teaching hospitals to ascertain the current use of antibiotics associated with surgery and to compare this use to the presently accepted standards. The survey included 300 consecutive surgical patients representing three surgical specialities. Evaluation was based on accepted therapeutic criteria with respect to the presence of an infection, appropriate in vitro antibiotic sensitivity testing, and recognized forms of prophylaxis. The results of our survey disclosed that although nonuse was usually appropriate, more often than not use of antibiotics was inappropriate. Errors, in order of frequency, included (1) misjudgments in attempted prophylaxis of operative wound infection, such as failure to use preoperative administration or use in clean operations without implanted foreign bodies, such as prosthesis, and (2) attempted treatment of undefined and undiagnosed fever.


Effects of Psychiatric Disorders on Labor Market Outcomes: A Latent Variable Approach Using Multiple Clinical Indicators.
In this paper, we estimate the effect of psychiatric disorders on labor market outcomes using a structural equation model with a latent index for mental illness, an approach that acknowledges the continuous nature of psychiatric disability. We also address the potential endogeneity of mental illness using an approach proposed by Lewbel (2012) that relies on heteroscedastic covariance restrictions rather than questionable exclusion restrictions for identification. Data come from the US National Comorbidity Survey - Replication and the National Latino and Asian American Study. We find that mental illness adversely affects employment and labor force participation and also reduces the number of weeks worked and increases work absenteeism. To assist in the interpretation of findings, we simulate the labor market outcomes of individuals meeting diagnostic criteria for mental disorder if they had the same mental health symptom profile as individuals not meeting diagnostic criteria. We estimate potential gains in employment for 3.5 million individuals, and reduction in workplace costs of absenteeism of $21.6 billion due to the resultant improvement in mental health. Copyright © 2015 John Wiley & Sons, Ltd.


Scent, sex, and the self-calibrating rat.
We propose that one mechanism whereby male rats,Rattus norvegicus, might gauge the reproductive condition of a female is by calibrating a stable odor with an odor that fluctuates through her reproductive cycle. We provide behavioral and histological evidence in support of such a self-calibration model. Male rats sniffed frequently at various body zones of females, and the proportion of sniffs deployed to each zone varied with the females' reproductive condition and relatedness. The females' haunches received more sniffs than any other part of their bodies, irrespective of their relatedness or reproductive condition. Furthermore, males tended to sniff the haunch after sniffing the forequarters, as part of a sequence of sniffing along a female from forequarters to hindquarters. Histology of the skin sebaceous glands indicated that the secretory activity of glands in the haunch, but not those in the forequarters, changed during estrus. Therefore, male rats had the opportunity to judge a female's reproductive status by calibrating the odor of her haunch against that of her forequarters. Self-calibration could represent a means of accommodating differences in odor within individuals.


Synthesis and biological evaluation of lipophilic teicoplanin pseudoaglycon derivatives containing a substituted triazole function.
A series of lipophilic teicoplanin pseudoaglycon derivatives, including alkyl-, aryl-, calixarene- and protected sugar-containing conjugates, were prepared using azide-alkyne click chemistry. Out of the conditions applied, the CuSO4-ascorbate reagent system proved to be more efficient than the Cu(I)I-Et3N-mediated reaction. Some of the new compounds have high in vitro activity against glycopeptide-resistant Gram-positive bacteria, including vanA-positive Enterococcus faecalis. A few of them also display promising in vitro anti-influenza activity.


Lead exposure during development results in increased neurofilament phosphorylation, neuritic beading, and temporal processing deficits within the murine auditory brainstem.
Low-level lead (Pb) exposure is a risk factor for learning disabilities, attention deficit hyperactivity disorder (ADHD), and other neurological dysfunction. It is not known how Pb produces these behavioral deficits, but low-level exposure during development is associated with auditory temporal processing deficits in an avian model, while hearing thresholds remain normal. Similar auditory processing deficits are found in children with learning disabilities and ADHD. To identify cellular changes underlying this functional deficit, Pb-induced alterations of neurons and glia within the mammalian auditory brainstem nuclei were quantified in control and Pb-exposed mice at postnatal day 21 by using immunohistochemistry, Western blotting, and 2D gel electrophoresis. Pb-treated mice were exposed to either 0.1 mM (low) or 2 mM (high) Pb acetate throughout gestation and through 21 days postnatally. Pb exposure results in little change in glial proteins such as glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), or F4/80 as determined by Western blot analysis and immunohistochemistry. In contrast, Pb exposure alters neuronal structural proteins by inducing increased phosphorylation of both the medium (NFM) and high-weight (NFH) forms of neurofilament within auditory brainstem nuclei. Axons immunolabeled for neurofilament protein show neuritic beading following Pb exposure both in vivo and in vitro, suggesting that Pb exposure also impairs axonal transport. Functional assessment shows no significant loss of peripheral function, but does reveal impairments in brainstem conduction time and temporal processing within the brainstem. These results provide evidence that Pb exposure during development alters axonal structure and function within brainstem auditory nuclei.


A decision tree model for the implementation of a safety strategy in the horse-racing industry.
The profession of a horse-racing jockey is a dangerous one. We developed a decision tree model quantifying the effects of implementing different safety strategies on jockey fall and injury rates and their associated costs. Data on race-day falls were obtained from stewards' reports from August 2002 to July 2009. Insurance claim data were provided by Principal Racing Authorities and workers' compensation authorities in each jurisdiction. Fall and claim incidence data were used as baseline rates. The model considered (1) the status quo, in which policy was unchanged; and (2) compared it with four hypothetical changes in policy that restricted apprentice jockeys from riding less-accomplished horses, with the aim of improving safety by reducing incidence of injurious jockey falls. Second-order Monte Carlo simulations were conducted to account for uncertainties. The point estimate for mean costs of falls under the status quo was $30.73/ride, with falls by apprentice jockeys with <250 career race rides riding horses with less than five race starts contributing the highest costs ($98.49/ride). The hypothetical safety strategies resulted in a 1.04%-5.07% decrease in fall rates versus status quo. For three of the four strategies, significant reductions of 8.74%-13.13% in workers' compensation costs over one single race season were predicted. Costs were highly sensitive to large claims. This model is a useful instrument for comparing potential changes in cost and risks associated with implementing new safety strategies in the horseracing industry.


A hydrologic network supporting spatially referenced regression modeling in the Chesapeake Bay Watershed.
The U.S. Geological Survey has developed a methodology for statistically relating nutrient sources and land-surface characteristics to nutrient loads of streams. The methodology is referred to as SPAtially Referenced Regressions On Watershed attributes (SPARROW), and relates measured stream nutrient loads to nutrient sources using nonlinear statistical regression models. A spatially detailed digital hydrologic network of stream reaches, stream-reach characteristics such as mean streamflow, water velocity, reach length, and travel time, and their associated watersheds supports the regression models. This network serves as the primary framework for spatially referencing potential nutrient source information such as atmospheric deposition, septic systems, point-sources, land use, land cover, and agricultural sources and land-surface characteristics such as land use, land cover, average-annual precipitation and temperature, slope, and soil permeability. In the Chesapeake Bay watershed that covers parts of Delaware, Maryland, Pennsylvania, New York, Virginia, West Virginia, and Washington D.C., SPARROW was used to generate models estimating loads of total nitrogen and total phosphorus representing 1987 and 1992 land-surface conditions. The 1987 models used a hydrologic network derived from an enhanced version of the U.S. Environmental Protection Agency's digital River Reach File, and course resolution Digital Elevation Models (DEMs). A new hydrologic network was created to support the 1992 models by generating stream reaches representing surface-water pathways defined by flow direction and flow accumulation algorithms from higher resolution DEMs. On a reach-by-reach basis, stream reach characteristics essential to the modeling were transferred to the newly generated pathways or reaches from the enhanced River Reach File used to support the 1987 models. To complete the new network, watersheds for each reach were generated using the direction of surface-water flow derived from the DEMs. This network improves upon existing digital stream data by increasing the level of spatial detail and providing consistency between the reach locations and topography. The hydrologic network also aids in illustrating the spatial patterns of predicted nutrient loads and sources contributed locally to each stream, and the percentages of nutrient load that reach Chesapeake Bay.


The Performance and Association Between Patient-reported and Performance-based Measures of Physical Functioning in Research on Individuals with Arthritis.
To evaluate the association between patient-reported outcome (PRO) and performance-based (PB) measures of physical functioning (PF) among individuals with self-identified arthritis to inform decisions of which to use when evaluating the effectiveness of a physical activity intervention. Secondary data analysis of a nonrandomized 2-arm pre-post community trial of 462 individuals who self-identified as having arthritis and participated in the Walk with Ease (WWE) intervention. Two PRO and 8 PB assessments were collected at baseline (preintervention) and at 6-week followup. We calculated correlations between PB and PRO measures, assessed how measures identified changes in PF from baseline to followup, and compared PRO and PB measures to arthritis symptoms of pain, stiffness, and fatigue. Strength of correlations between PB and PRO measures varied depending on the PB measure, ranging from 0.21 to 0.54. PRO and PB measures identified PF improvements from baseline to followup, but none showed significant differences between the 2 WWE modalities (instructor-led or self-directed groups). Correlations with arthritis symptoms were stronger for PRO (0.30-0.46) than PB measures (0.03-0.31). PRO measures may provide us with insights into aspects of PF that are not identified by PB measures alone. Use of PRO measures allows patients to communicate their perceptions of PF, which may provide a more accurate representation of overall PF. Our study does not suggest abandoning the use of PB measures to characterize PF in patients with self-identified arthritis, but recommends that PRO measures may serve as complementary or surrogate endpoints for some studies.


Integrated polarization rotator/converter by stimulated Raman adiabatic passage.
We proposed a polarization rotator inspired by stimulated Raman adiabatic passage model from quantum optics, which is composed of a signal waveguide and an ancillary waveguide. The two orthogonal modes in signal waveguide and the oblique mode in ancillary waveguide form a Λ-type three-level system. By controlling the width of signal waveguide and the gap between two waveguides, adiabatic conversion between two orthogonal modes can be realized in the signal waveguide. With such adiabatic passage, polarization conversion is completed within 150 μm length, with the efficiencies over 99% for both conversions between horizontal polarization and vertical polarization. In addition, such a polarization rotator is quite robust against fabrication error, allowing a wide range of tolerances for the rotator geometric parameters. Our work is not only significative to photonic simulations of coherent quantum phenomena with engineered photonic waveguides, but also enlightens the practical applications of these phenomena in optical device designs.


A framework for inferring fitness landscapes of patient-derived viruses using quasispecies theory.
Fitness is a central quantity in evolutionary models of viruses. However, it remains difficult to determine viral fitness experimentally, and existing in vitro assays can be poor predictors of in vivo fitness of viral populations within their hosts. Next-generation sequencing can nowadays provide snapshots of evolving virus populations, and these data offer new opportunities for inferring viral fitness. Using the equilibrium distribution of the quasispecies model, an established model of intrahost viral evolution, we linked fitness parameters to the composition of the virus population, which can be estimated by next-generation sequencing. For inference, we developed a Bayesian Markov chain Monte Carlo method to sample from the posterior distribution of fitness values. The sampler can overcome situations where no maximum-likelihood estimator exists, and it can adaptively learn the posterior distribution of highly correlated fitness landscapes without prior knowledge of their shape. We tested our approach on simulated data and applied it to clinical human immunodeficiency virus 1 samples to estimate their fitness landscapes in vivo. The posterior fitness distributions allowed for differentiating viral haplotypes from each other, for determining neutral haplotype networks, in which no haplotype is more or less credibly fit than any other, and for detecting epistasis in fitness landscapes. Our implemented approach, called QuasiFit, is available at http://www.cbg.ethz.ch/software/quasifit.


Comparative study of predictive computational models for nanoparticle-induced cytotoxicity.
With the increasing use of nanomaterials incorporated into consumer products, there is a need for developing approaches to establish "quantitative structure-activity relationships" (QSARs). These relationships could be used to predict various biological responses after exposure to nanomaterials for the purposes of risk analysis. This risk analysis is applicable to manufacturers of nanomaterials in an effort to determine potential hazards. Because metal oxide materials are some of the most widely applicable and studied nanoparticle types for incorporation into cosmetics, food packaging, and paints and coatings, we focused on comparing different approaches for establishing QSARs for this class of materials. Metal oxide nanoparticles are believed, by some, to cause alterations in cellular function due to their size and/or surface area. Others have said that these nanomaterials, because of the oxidized state of the metal, do not induce stress in biological tests systems. This controversy highlights the need to systematically develop structure-activity relationships (i.e., the relationship between physicochemical features to the cellular responses) and tools for predicting potential biological effects after a metal oxide nanomaterial exposure. Here, we attempt to identify a set of properties of two specific metal oxide nanomaterials-TiO(2) and ZnO-that could be used to characterize and predict the induced cellular membrane damage of immortalized human lung epithelial cells. We adopt a mathematical modeling approach that uses the engineered nanomaterial size characterized as a dry nanopowder and the nanomaterial behavior in ultrapure water, phosphate buffer, and cell culture media to predict nanomaterial-induced cellular membrane damage (via lactate dehydrogenase release). Results of these studies provide insights on how engineered nanomaterial features influence cellular responses and thereby outline possible approaches for developing and applying predictive computational models for biological responses caused by exposure to nanomaterials.


Adaptation and failure of pancreatic beta cells in murine models with different degrees of metabolic syndrome.
The events that contribute to the expansion of beta-cell mass and enhanced beta-cell function in insulin-resistant states have not been elucidated fully. Recently, we showed that beta-cell adaptation failed dramatically in adult, insulin-resistant POKO mice, which contrasts with the appropriate expansion of beta cells in their ob/ob littermates. Thus, we hypothesised that characterisation of the islets in these mouse models at an early age should provide a unique opportunity to: (1) identify mechanisms involved in sensing insulin resistance at the level of the beta cells, (2) identify molecular effectors that contribute to increasing beta-cell mass and function, and (3) distinguish primary events from secondary events that are more likely to be present at more advanced stages of diabetes. Our results define the POKO mouse as a model of early lipotoxicity. At 4 weeks of age, it manifests with inappropriate beta-cell function and defects in proliferation markers. Other well-recognised pathogenic effectors that were observed previously in 16-week-old mice, such as increased reactive oxygen species (ROS), macrophage infiltration and endoplasmic reticulum (ER) stress, are also present in both young POKO and young ob/ob mice, indicating the lack of predictive power with regards to the severity of beta-cell failure. Of interest, the relatively preserved lipidomic profile in islets from young POKO mice contrasted with the large changes in lipid composition and the differences in the chain length of triacylglycerols in the serum, liver, muscle and adipose tissue in adult POKO mice. Later lipotoxic insults in adult beta cells contribute to the failure of the POKO beta cell. Our results indicate that the rapid development of insulin resistance and beta-cell failure in POKO mice makes this model a useful tool to study early molecular events leading to insulin resistance and beta-cell failure. Furthermore, comparisons with ob/ob mice might reveal important adaptive mechanisms in beta cells with either therapeutic or diagnostic potential.


Time for a culture change? Suboptimal compliance with blood culture standards at a district hospital in Cape Town.
The benchmark for contaminated blood cultures (BCs) is 3%. The South African (SA) guideline aims to optimise BC yield and reduce contamination. Data on BC collection practices in SA since the publication of the 2010 SA guideline are lacking. To evaluate compliance with the national guideline for the optimal use of BCs and determine the BC contamination rate at a local district hospital. An audit of compliance with 22 BC standards was conducted at a district hospital in Cape Town, SA. Standards were evaluated by reviewing clinical and laboratory data and by a clinician questionnaire. Of the 425 BCs reviewed, 12.5% had positive growth, and 4.5% grew contaminants. Only 33% of BC bottles contained the recommended fill volume of 8-10 mL, and 96.9% of patients had a single BC within a 24-hour period. Of all the BCs, only 7.8% had a combined blood volume of at least 20 mL. The yield of pathogens in BCs collected after antibiotic exposure was 4.9% compared with 7.5% for those cultures with no prior antibiotic exposure (p=0.3). The overall median needle-to-incubator transport time was 11 hours 25 minutes. The BC contamination rate was high and compliance with most standards was variable or not met. The findings may not be generalisable to other hospitals, and we recommend that each institution reviews its own BC practices. Recommendations made to hospital staff included a re-audit following implementation of these recommendations.


A review of breast cancer pathology reports in Nigeria.
Diagnosis and treatment of cancer rely heavily on imaging, histopathology and molecular information. Incomplete or missing tumour information can hinder the delivery of high-quality care in oncology practice, especially in resource-limited countries. To evaluate the completeness of histopathology reporting in a real-world setting and identify areas for future cancer care delivery research efforts, we retrospectively analysed reports from patients diagnosed with breast cancer who received care at a high-volume oncology department at a hospital in Lagos, Nigeria. Demographic, institutional and histopathology characteristics were retrospectively obtained from 1,001 patient records from 2007 to 2016. Completeness was defined as reporting five tumour features (tumour histology, tumour grade, laterality, oestrogen receptor (ER) or progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2)) for biopsy specimens and seven tumour features (tumour size, tumour histology, tumour grade, laterality, ER/PR, HER2 and lymph node involvement) for surgical specimens. The mean age of patients was 48.6 ± 11.7 years with a predominantly female population (99.3%). A majority of pathologic reports were produced after 2011, and two-thirds of the reports originated from centres or labs within Lagos, Nigeria (67.7%). Most reports documented primary site (98.0%) and specimen type (85.0%) while other characteristics were less often recorded. This led to substantial variation in reporting between biopsy (13.4%) and surgical (6.1%) specimens for an overall low pathology report completeness <10%. The majority of patient records analysed lacked complete documentation of breast cancer histopathological characteristics commonly used in oncology practice. Our study highlights a need to identify and address the contributing factors for incomplete histopathological reporting in Nigeria and will guide future clinical programmatic developments.


A cohort study of mortality among Ontario pipe trades workers.
To study mortality in a cohort of members of the United Association of Journeymen and Apprentices of the Plumbing and Pipe Fitting Industry of the United States and Canada and to compare results with two previous proportional mortality studies. A cohort of 25,285 workers who entered the trade after 1949 was assembled from records of the international head office. Mortality was ascertained by linkage to the Canadian Mortality Registry at Statistics Canada. Standardised mortality ratios were computed using Ontario general population mortality rates as the reference. There were significant increases in lung cancer mortality rates (SMR 1.27; 95% CI 1.13 to 1.42). Increased lung cancer risk was observed among plumbers, pipefitters, and sprinkler fitters. Increased risk was observed among workers joining the Union as late as the 1970s. A random effects meta-analysis of this study and the two PMR studies found significant increases in oesophageal (RR 1.24; 95% CI 1.00 to 1.53), lung (RR 1.31; 95% CI 1.19 to 1.44), and haematological/lymphatic (RR 1.21; 95% CI 1.08 to 1.35) malignancies. The mortality pattern is consistent with the effects of occupational exposure to asbestos. Increased risk due to other respiratory carcinogens such as welding fume cannot be excluded. There are substantial amounts of asbestos in place in industrial and commercial environments. The education and training of workers to protect themselves against inhalation hazards will be necessary well into the future.


Food insecurity and nutritional biomarkers in relation to stature in Inuit children from Nunavik.
Inuit in Canada experience alarming levels of food insecurity, but nutritional and physiological consequences are poorly documented, especially in school-age children. The objective of this study was to assess the relation of food insecurity to iron deficiency and stature in school-aged Inuit children from Nunavik (Northern Quebec). Food insecurity, iron deficiency, and stature were assessed in a cohort of children. Food insecurity was determined by interviewing the children's mothers. Multiple logistic regression was used to evaluate the association of food insecurity to iron deficiency and short stature. We defined short stature as a height in the lowest tertile for age and sex, based on Canadian growth charts. The relation of food insecurity to height (cm) was analyzed with a general linear model. Statistical models controlled for age, sex, normal/overweight/obese status, prenatal lead exposure and postnatal polychlorinated biphenyls exposure. Half of the children (49.7%, n=145) were food insecure, while one third were iron depleted, 12.6% had anaemia, and 8.7% had iron-deficiency anaemia. The multivariate odds ratio of anaemia was 1.82 (95% CI: 0.97, 3.42, p=0.06) for food-insecure children. Prevalence of short stature was 18.7%. Food-insecure children were an average of 2 cm shorter (95% CI: -0.48, -3.17) than food-secure children (p<0.01). In this population, food-insecure children have greater burdens of nutritional deficiencies and slower linear growth. Considering the high prevalence of food insecurity among Inuit children in Nunavik, nutritional deficiencies and adverse effects on development should be carefully monitored.


Degradation of 14C-glyphosate and aminomethylphosphonic acid (AMPA) in three agricultural soils.
Glyphosate (N-phosphonomethyl glycine) is the most used herbicide worldwide. The degradation of 14C-labeled glyphosate was studied under controlled laboratory conditions in three different agricultural soils: a silt clay loam, a clay loam and a sandy loam soil. The kinetic and intensity of glyphosate degradation varied considerably over time within the same soil and among different types of soil. Our results demonstrated that the mineralization rate of glyphosate was high at the beginning of incubation and then decreased with time until the end of the experiment. The same kinetic was observed for the water extractable residues. The degradation of glyphosate was rapid in the soil with low adsorption capacity (clay loam soil) with a short half-life of 4 days. However, the persistence of glyphosate in high adsorption capacity, soils increased, with half-live of 19 days for silt clay loam soil and 14.5 days for sandy loam soil. HPLC analyses showed that the main metabolite of glyphosate, aminomethylphosphonic acid (AMPA) was detected after three days of incubation in the extracts of all three soils. Our results suggested that the possibility of contamination of groundwater by glyphosate was high on a long-term period in soils with high adsorption capacity and low degrading activities and/or acid similar to sandy loam soil. This risk might be faster but less sustainable in soil with low adsorption capacity and high degrading activity like the clay loam soil. However, the release of non-extractable residues may increase the risk of contamination of groundwater regardless of the type of soil.


Pain in infants who are younger than 2 months during suprapubic aspiration and transurethral bladder catheterization: a randomized, controlled study.
Proper diagnosis of urinary tract infections depends on obtaining an uncontaminated urine sample for culture. Suprapubic aspiration and transurethral catheterization are the 2 recommended procedures for obtaining specimens for urine culture from young infants. The objective of the current study was to compare the pain that is experienced during these 2 procedures when performed in young infants. A prospective, single-blind, randomized, controlled study was conducted at a university-affiliated hospital in Israel. Institutional Research Ethics Board approved the study. Infants who were 0 to 2 months of age and presented to the emergency department with fever and therefore required urine collection for culture were randomly assigned evenly into 2 sample collection groups: suprapubic aspiration or transurethral catheterization. Patients were excluded when they were born prematurely or had had a previous sepsis workup or other painful procedures or an anomaly of the urogenital system or abdominal wall. Eutectic mixture of local anesthetic cream that contained lidocaine and prilocaine was applied 1 hour before the procedure. The urethra was catheterized using a 5-Fr latex-free feeding tube that was lubricated with sterile water-soluble jelly that contained 2% lidocaine hydrochloride. Pediatric residents who were experienced with the procedures performed both suprapubic aspiration and transurethral catheterization. The parents were instructed to use any comfort strategies that they wished, including verbal or physical comforting and pacifiers. Pain during collection was assessed on a 100-mm visual analog scale by a nurse and a parent. In addition, the infant's upper part of the body was videotaped during the procedure. An investigator, who was blinded to the procedure, assigned a point score according to the Douleur Aigue du Nouveaune neonatal acute pain scale. For ensuring a successful blinding process, the following steps were taken. First, camera recording started 30 seconds before the procedure to prevent the possibility of distinguishing between the procedures on the basis of their duration. Second, the physician and the nurse were asked not to speak during the procedure to avoid revealing the nature of the procedure. Third, the person who videotaped the procedure watched the tape before it was analyzed to ensure the impossibility of identifying the procedure from the tape. The Student's t test was used to compare the groups. The primary outcome was the mean Douleur Aigue du Nouveaune score. Secondary outcomes were the mean visual analogue scale for pain as estimated by the parents and by the nurse. We estimated that 25 patients would be needed in each group to detect a difference in the mean Douleur Aigue du Nouveaune score of at least 2 points with a power of 80% and alpha of .05. The study was conducted between April 1, 2004, and April 30, 2005. Fifty-eight infants were recruited; 29 were randomly assigned to suprapubic aspiration, and 29 were randomly assigned to transurethral catheterization. Seven infants were excluded because of consent withdrawal (3 patients), because of technical difficulties during videotaping (3 patients), or because the child voided during the procedure (1 patient). Twenty-seven infants in the suprapubic aspiration group and 24 in the transurethral catheterization group completed the study. All male infants were circumcised. An adequate urine sample was obtained in 18 (66%) of 27 patients in the suprapubic aspiration group and in 20 (83.3%) of 24 in the transurethral catheterization group. The mean Douleur Aigue du Nouveaune score was significantly higher in patients who were randomly assigned to suprapubic aspiration compared with patients who were randomly assigned to transurethral catheterization (7 and 4.5, respectively). The differences in Douleur Aigue du Nouveaune score also were significant in a subgroup analysis of boys and girls. Mean visual analogue scale scores by parents was higher in the suprapubic aspiration group compared with transurethral catheterization (63 +/- 27 mm vs 46 +/- 26, respectively). Similarly, mean visual analogue scale scores by nurses was higher in the suprapubic aspiration group compared with transurethral catheterization (3 +/- 18 mm vs 43 +/- 25 mm, respectively). In infants who are younger 2 months, suprapubic aspiration is more painful than transurethral catheterization. Health professionals should consider these differences when choosing a method for obtaining a urine sample from young infants.


Rho and Rho-kinase activity in adipocytes contributes to a vicious cycle in obesity that may involve mechanical stretch.
The development of obesity involves multiple mechanisms. Here, we identify adipocyte signaling through the guanosine triphosphatase Rho and its effector Rho-kinase as one such mechanism. Mice fed a high-fat diet (HFD) showed increased Rho-kinase activity in adipose tissue compared to mice fed a low-fat diet. Treatment with the Rho-kinase inhibitor fasudil attenuated weight gain and insulin resistance in mice on a HFD. Transgenic mice overexpressing an adipocyte-specific, dominant-negative form of RhoA (DN-RhoA TG mice) showed decreased Rho-kinase activity in adipocytes, decreased HFD-induced weight gain, and improved glucose metabolism compared to wild-type littermates. Furthermore, compared to HFD-fed wild-type littermates, DN-RhoA TG mice on a HFD showed decreased adipocyte hypertrophy, reduced macrophage recruitment to adipose tissue, and lower expression of mRNAs encoding various adipocytokines. Lipid accumulation in cultured adipocytes was associated with increased Rho-kinase activity and increased abundance of adipocytokine transcripts, which was reversed by a Rho-kinase inhibitor. Direct application of mechanical stretch to mature adipocytes increased Rho-kinase activity and stress fiber formation. Stress fiber formation, which was also observed in adipocytes from HFD-fed mice, was prevented by Rho-kinase inhibition and in DN-RhoA TG mice. Our findings indicate that lipid accumulation in adipocytes activates Rho to Rho-kinase (Rho-Rho-kinase) signaling at least in part through mechanical stretch and implicate Rho-Rho-kinase signaling in inflammatory changes in adipose tissue in obesity. Thus, inhibition of Rho-Rho-kinase signaling may provide a therapeutic strategy for disrupting a vicious cycle of adipocyte stretch, Rho-Rho-kinase signaling, and inflammation of adipose tissue that contributes to and aggravates obesity.


Discontinuation syndrome in newborns whose mothers took antidepressants while pregnant or breastfeeding.
This study compared mothers' report of symptoms of discontinuation syndrome in infants exposed to antidepressants both in utero and during lactation to infants who were exposed only during lactation. This is a convenience sample of 930 women breastfeeding women who answered an online questionnaire about antidepressant use while pregnant and breastfeeding. All 930 women had taken antidepressants while breastfeeding, and 527 had also taken antidepressants during pregnancy. There were no participants in the present study who had taken antidepressants only during pregnancy. The questionnaire was posted on the first author's Medications and Breastfeeding Forum. There was no advertising of this study, nor were efforts made to recruit women into this study beyond posting a notice on the website. The questionnaire included a list of symptoms that mothers may have observed in their infants during the newborn period, as well as demographic questions, and questions about antidepressant use during pregnancy and lactation. The majority of women reported that their infants never experienced the symptoms of discontinuation syndrome. Twenty-five percent reported infant irritability. A smaller percentage reported inconsolable crying (17%), low body temperature (14%), and significant problems with eating and sleeping (15%). Logistic regression revealed that mothers who took antidepressants while pregnant and then during breastfeeding were two to eight times more likely to report symptoms of discontinuation syndrome than women who took them only while breastfeeding. Discontinuation symptoms were more likely to occur in infants whose mothers took medications with shorter half-lives. Discontinuation syndrome does occur in a small percentage of infants exposed to antidepressants in utero. Mothers reported a higher frequency of discontinuation syndrome after in utero exposure followed by breastfeeding than when infants were exposed to antidepressants only during lactation.


Prevalence and risk factors of HIV infection among people who inject drugs in Cambodia: findings from a national survey.
Globally, people who inject drugs (PWID) continue to be among the most vulnerable populations to acquire infection of human immunodeficiency virus (HIV). The most recent national survey found that nearly a quarter of PWID in Cambodia were infected with HIV in 2012. The aim of this study is to estimate the current prevalence of and factors associated with HIV infection among PWID in Cambodia. This national integrated biological and behavioral survey was conducted from June to December 2017. Participants were recruited from the capital city and 11 major provinces using the respondent driven sampling method. Face-to-face interviews were conducted using a structured questionnaire, and blood samples were collected for HIV, syphilis, and hepatitis C virus (HCV) testing. Multiple logistic regression analysis was conducted to identify risk factors for HIV infection. All analyses were estimated with sampling weights that corrected for non-response and sample design. A total of 310 PWID participated in the study, and the mean age was 31.8 years (SD = 7.8). The prevalence of HIV was 15.2%. More than half (57.4%) of the HIV-positive participants were co-infected with HCV, and 44.7% were not aware of their HIV status prior to this study. After adjustment for other covariates, HIV infection remained positively associated with being female (AOR = 1.88, 95% CI = 1.03-4.04), being in the older age group of ≥35 (AOR = 2.99, 95% CI 1.33-9.22), being widowed, divorced or separated (AOR = 2.57, 95% CI = 1.04-6.67), living on the streets (AOR = 2.86, 95% CI 1.24-4.37), and HCV infection (AOR = 3.89, 95% CI 1.86-1.15). The HIV infection remained negatively associated with having higher level of formal education of ≥10 years (AOR = 0.44, 95% CI 0.13-0.83) and higher average income of ≥US$200 per month (AOR = 0.20, 95% CI = 0.05-0.74). The prevalence of HIV among PWID in Cambodia remains high, but is reducing compared with the 24.8% reported in the 2012 national survey. Findings from this study provide critical information for tailoring interventions based on identified vulnerabilities and risk factors for HIV. Our findings underline the importance of socio-structural factors in HIV epidemiology among PWID in Cambodia, which require mitigation.


Beyond a neurotransmitter: The role of serotonin in inflammation and immunity.
Serotonin (5-HT), a well-known neurotransmitter in the brain, also plays an important role in peripheral tissues, including the immune system. There is a growing body of evidence suggesting that many different types of immune cells express the machinery to generate, store, respond to and/or transport serotonin, including T cells, macrophages, mast cells, dendritic cells and platelets. In addition, there is emerging evidence of a possible connection between T cells, serotonin and mood disorders. How 5-HT interacts with the peripheral immune system and if this signaling is associated with behavioral phenotypes found in mood disorders like major depressive disorder (MDD) is not well understood. In this review, we summarize the existing literature on what is known about the link between 5-HT and the immune system and the effects of 5-HT signaling on different cells of the peripheral immune system, with a particular focus on T cells. In addition, we review the current evidence that peripheral immune system alterations and CNS function may be interrelated and the possible implications of these findings for drug discovery.


The dissociation of nuclear proteins from superhelical DNA.
Structures retaining many of the morphological features of nuclei may be released by gently lysing human cells in solutions containing non-ionic detergents and high concentrations of salt. These nucleoids contain superhelical DNA. Using a double-labelling procedure we have compared, at different salt concentrations, the amounts and types of protein associated with human nucleoides containings superhelical or relaxed DNA. We find that the slightly lysine-rich histones (H2A and H2B) but not the arginine-rich histones (H3 and H4) dissociate more slowly from nucleoids containing superhelical DNA than from those containing relaxed DNA. A protein of apparent molecular weight of 22000 also binds more tightly to superhelical DNA. We conclude that this protein and the slightly lysine-rich histones transmute free energy of supercoiling into binding energy when they bind to superhelical DNA.


"Do grandmas have husbands?" Generational memory and twentieth-century women's lives.
This essay uses memory in the ancient and modern sense of the "inner life of thought" to describe the formation of generational memory in a modern professional family whose twentieth-century history has been fractured by migration, war, education, and divorce. It is about the power of feeling and law, which framed the practical freedoms of twentieth-century women's lives and introduced the modern citizen in the aftermath of universal suffrage and world war. The first part of the essay emphasizes the psychic dimension of bodily feeling and drive in the formation of memory; a dimension overlooked by oral history and social movements, yet confirmed by autobiography and memoir. My granddaughter's questions provoked resistance as well as family stories, and let me observe the thought process in a child. Social history, autobiography, and personal memory confirm the common experience of everyday life reaching back through generations of London families; folklore, commerce, and family story make narratives of dreams, hopes, terrors, and events; a child's comprehension of the outside world is grasped through curiosity, imagination, and play in which bodily feeling is as powerful as speech and prohibition to make meanings that flow between inner world and external reality. The second half of the essay reflects on Joan Riviere's description of the self. Leading British psychoanalyst, translator of Freud, writing in the 1950s, Riviere's language of the inner world resonates with the liberal social ethics -- empathy, public service, common good -- which underpinned women's and human rights mid-twentieth century and the egalitarian and reproduction reforms whose universalism has been challenged since the 1970s. Negative feeling is striking in Riviere's description of the self -- fear, shame, shock, and trauma, which are confirmed in memoir and autobiography. In contrast, liberal social democratic accounts of the time idealized English character. Today, the future uncertain, memory -- in the ancient and modern sense of the "inner eye of thought" -- is more than ever necessary for social movements as for the individual.


Microfluidic White Organic Light-Emitting Diode Based on Integrated Patterns of Greenish-Blue and Yellow Solvent-Free Liquid Emitters.
We demonstrated a novel microfluidic white organic light-emitting diode (microfluidic WOLED) based on integrated sub-100-μm-wide microchannels. Single-μm-thick SU-8-based microchannels, which were sandwiched between indium tin oxide (ITO) anode and cathode pairs, were fabricated by photolithography and heterogeneous bonding technologies. 1-Pyrenebutyric acid 2-ethylhexyl ester (PLQ) was used as a solvent-free greenish-blue liquid emitter, while 2,8-di-tert-butyl-5,11-bis(4-tert-butylphenyl)-6,12-diphenyltetracene (TBRb)-doped PLQ was applied as a yellow liquid emitter. In order to form the liquid white light-emitting layer, the greenish-blue and yellow liquid emitters were alternately injected into the integrated microchannels. The fabricated electro-microfluidic device successfully exhibited white electroluminescence (EL) emission via simultaneous greenish-blue and yellow emissions under an applied voltage of 100 V. A white emission with Commission Internationale de l'Declairage (CIE) color coordinates of (0.40, 0.42) was also obtained; the emission corresponds to warm-white light. The proposed device has potential applications in subpixels of liquid-based microdisplays and for lighting.


Aurantimonas manganoxydans, sp. nov. and Aurantimonas litoralis, sp. nov.: Mn(II) oxidizing representatives of a globally distributed clade of alpha-Proteobacteria from the order Rhizobiales.
Several closely related Mn(II)-oxidizing alpha-Proteobacteria were isolated from very different marine environments: strain SI85-9A1 from the oxic/anoxic interface of a stratified Canadian fjord, strain HTCC 2156 from the surface waters off the Oregon coast, and strain AE01 from the dorsal surface of a hydrothermal vent tubeworm. 16S rRNA analysis reveals that these isolates are part of a tight phylogenetic cluster with previously characterized members of the genus Aurantimonas. Other organisms within this clade have been isolated from disparate environments such as surface waters of the Arctic and Mediterranean seas, a deep-sea hydrothermal plume, and a Caribbean coral. Further analysis of all these strains revealed that many of them are capable of oxidizing dissolved Mn(II) and producing particulate Mn(III/IV) oxides. Strains SI85-9A1 and HTCC 2156 were characterized further. Despite sharing nearly identical 16S rRNA gene sequences with the previously described Aurantimonas coralicida, whole genome DNA-DNA hybridization indicated that their overall genomic similarity is low. Polyphasic phenotype characterization further supported distinguishing characteristics among these bacteria. Thus SI85-9A1 and HTCC 2156 are described as two new species within the family 'Aurantimionadaceae': Aurantimonas manganoxydans sp. nov. and Aurantimonas litoralis sp. nov. This clade of bacteria is widely distributed around the globe and may be important contributors to Mn cycling in many environments. Our results highlight the difficulty in utilizing 16S rRNA-based approaches to investigate the microbial ecology of Mn(II) oxidation.


Returning from oblivion: imaging the neural core of consciousness.
One of the greatest challenges of modern neuroscience is to discover the neural mechanisms of consciousness and to explain how they produce the conscious state. We sought the underlying neural substrate of human consciousness by manipulating the level of consciousness in volunteers with anesthetic agents and visualizing the resultant changes in brain activity using regional cerebral blood flow imaging with positron emission tomography. Study design and methodology were chosen to dissociate the state-related changes in consciousness from the effects of the anesthetic drugs. We found the emergence of consciousness, as assessed with a motor response to a spoken command, to be associated with the activation of a core network involving subcortical and limbic regions that become functionally coupled with parts of frontal and inferior parietal cortices upon awakening from unconsciousness. The neural core of consciousness thus involves forebrain arousal acting to link motor intentions originating in posterior sensory integration regions with motor action control arising in more anterior brain regions. These findings reveal the clearest picture yet of the minimal neural correlates required for a conscious state to emerge.


Sugar and stroke: cerebrovascular disease and blood glucose control.
In this review we will discuss the cerebrovascular consequences of dysglycemia and current evidence for therapy, making reference to recent work in the fields of neuropathology, epidemiology, and relevant clinical trial data. Prospective observational and clinical trial data show a clear association between diabetes mellitus and vascular disease, which extends to cerebrovascular disease. The benefits of intervention to lower blood glucose in terms of microvascular health are well established but benefit on macrovascular, especially cerebrovascular, health has been less apparent. Recent large-scale trials and metaanalyses have helped us to better define the role of glycemic control in macrovascular disease. Although few studies of glycemic therapy have used cerebrovascular disease as a primary endpoint, stroke-specific data can be derived. Associations between blood glucose and outcome are also apparent for acute stroke. A period of hyperglycemia is common, with elevated blood glucose in the periinfarct period consistently linked with poor outcome in patients with and without diabetes. The mechanisms that underlie this deleterious effect of dysglycemia on ischemic neuronal tissue remain to be established, although in vitro research, functional imaging, and animal work have provided clues. While prompt correction of hyperglycemia can be achieved, trials of acute insulin administration in stroke and other critical care populations have been equivocal. Diabetes mellitus and hyperglycemia per se are associated with poor cerebrovascular health, both in terms of stroke risk and outcome thereafter. Interventions to control blood sugar are available but evidence of cerebrovascular efficacy are lacking. In diabetes, glycemic control should be part of a global approach to vascular risk while in acute stroke, theoretical data suggest intervention to lower markedly elevated blood glucose may be of benefit, especially if thrombolysis is administered. Trials have been underpowered to demonstrate treatment effect and any intervention must be balanced against risk of hypoglycemia.


Body size variation in insects: a macroecological perspective.
Body size is a key feature of organisms and varies continuously because of the effects of natural selection on the size-dependency of resource acquisition and mortality rates. This review provides a critical and synthetic overview of body size variation in insects from a predominantly macroecological (large-scale temporal and spatial) perspective. Because of the importance of understanding the proximate determinants of adult size, it commences with a brief summary of the physiological mechanisms underlying adult body size and its variation, based mostly on findings for the model species Drosophila melanogaster and Manduca sexta. Variation in nutrition and temperature have variable effects on critical weight, the interval to cessation of growth (or terminal growth period) and growth rates, so influencing final adult size. Ontogenetic and phylogenetic variation in size, compensatory growth, scaling at the intra- and interspecific levels, sexual size dimorphism, and body size optimisation are then reviewed in light of their influences on individual and species body size frequency distributions. Explicit attention is given to evolutionary trends, including gigantism, Cope's rule and the rates at which size change has taken place, and to temporal ecological trends such as variation in size with succession and size-selectivity during the invasion process. Large-scale spatial variation in size at the intraspecific, interspecific and assemblage levels is considered, with special attention being given to the mechanisms proposed to underlie clinal variation in adult body size. Finally, areas particularly in need of additional research are identified.


Microbial Consortia Engineering for Cellular Factories: in vitro to in silico systems.
This mini-review discusses the current state of experimental and computational microbial consortia engineering with a focus on cellular factories. A discussion of promising ecological theories central to community resource usage is presented to facilitate interpretation of consortial designs. Recent case studies exemplifying different resource usage motifs and consortial assembly templates are presented. The review also highlights in silico approaches to design and to analyze consortia with an emphasis on stoichiometric modeling methods. The discipline of microbial consortia engineering possesses a widely accepted potential to generate highly novel and effective bio-catalysts for applications from biofuels to specialty chemicals to enhanced mineral recovery.


Tall height and obesity are associated with an increased risk of aggressive prostate cancer: results from the EPIC cohort study.
The relationship between body size and prostate cancer risk, and in particular risk by tumour characteristics, is not clear because most studies have not differentiated between high-grade or advanced stage tumours, but rather have assessed risk with a combined category of aggressive disease. We investigated the association of height and adiposity with incidence of and death from prostate cancer in 141,896 men in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Multivariable-adjusted Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). After an average of 13.9 years of follow-up, there were 7024 incident prostate cancers and 934 prostate cancer deaths. Height was not associated with total prostate cancer risk. Subgroup analyses showed heterogeneity in the association with height by tumour grade (P heterogeneity = 0.002), with a positive association with risk for high-grade but not low-intermediate-grade disease (HR for high-grade disease tallest versus shortest fifth of height, 1.54; 95% CI, 1.18-2.03). Greater height was also associated with a higher risk for prostate cancer death (HR = 1.43, 1.14-1.80). Body mass index (BMI) was significantly inversely associated with total prostate cancer, but there was evidence of heterogeneity by tumour grade (P heterogeneity = 0.01; HR = 0.89, 0.79-0.99 for low-intermediate grade and HR = 1.32, 1.01-1.72 for high-grade prostate cancer) and stage (P heterogeneity = 0.01; HR = 0.86, 0.75-0.99 for localised stage and HR = 1.11, 0.92-1.33 for advanced stage). BMI was positively associated with prostate cancer death (HR = 1.35, 1.09-1.68). The results for waist circumference were generally similar to those for BMI, but the associations were slightly stronger for high-grade (HR = 1.43, 1.07-1.92) and fatal prostate cancer (HR = 1.55, 1.23-1.96). The findings from this large prospective study show that men who are taller and who have greater adiposity have an elevated risk of high-grade prostate cancer and prostate cancer death.


Hygiene hypothesis: innate immunity, malaria and multiple sclerosis.
The establishment of new hygienic conditions plays a role in the appearance of autoimmunity in "westernalised" countries. Consistently, but still unconvincingly, several epidemiological and immunogenetic evidences link the disappearance of malaria with the increase of multiple sclerosis (MS) in Sardinia, insular Italy. To this purpose, we have made an attempt to build a relationship between malaria disappearance and MS under the light of the hygiene hypothesis. This relationship has taken into account the MS frequency increase soon after malaria eradication in Sardinia, the present malaria endemism in Africa, the innate immune system activity here represented by Chitotriosidase (Chit), an hydrolytic enzyme produced by macrophages, and an unproductive polymorphism of Chit gene (CHIT1) as a measure of the genetic weight of Plasmodium-related immunity in these populations. Data were derived from both experimental results specifically designed for this study and other data obtained from the available literature. The experimental and the hystorical-epidemiological findings concur to indicate that whilst in Africa CHIT1 mutation is rare and MS incidence is very low due to unmodified parasitic influence and hygienic conditions, in Sardinia a relationships between CHIT1 mutation, plasma Chit activity and MS prevalence rate is detected, even to a higher extent compared to Sicily, area at former lower rate of malaria endemy. Upon such a basis, we have found convincing argumentations that, at least in part, MS has increased over the last four decades in Sardinia also because of the eradication of malaria, 50 years ago. This infectious disease that run for centuries in Sardinia, besides well documented enzyme deficiencies and red cell pathologies, have left an abnormal macrophage reactivity against Plasmodium falciparum. As a result, some Sardinian individuals secrete abnormally high levels of mediators of the innate immunity, relics of former protective anti-malaria infection, in response to new environmental factors. Therefore, MS, an immune-conditioned pathology of the central nervous system has been subject to an unexplained epidemiological increase in the last few decades in Sardinia because cells of the innate immune system, immuno-genetically selected over the centuries in response to widespread P. falciparum malaria, have kept the tendency to over-respond to triggering factors even after the disappearance of malaria. This hypothesis may have an influence in re-directing clinicians toward a innate immunity-based rather than an antigen specific-based new MS therapies.


Influence of Gastric Emptying and Gut Transit Testing on Clinical Management Decisions in Suspected Gastroparesis.
Gastric emptying scintigraphy (GES) or wireless motility capsules (WMCs) can evaluate upper gastrointestinal symptoms in suspected gastroparesis; WMC tests can also investigate lower gut symptoms. We aimed to determine whether these tests impact treatment plans and needs for additional diagnostic evaluation. In a prospective, multicenter study, 150 patients with gastroparesis symptoms simultaneously underwent GES and WMC testing. Based on these results, investigators devised management plans to recommend changes in medications, diet, and surgical therapies and order additional diagnostic tests. Treatment changes were recommended more often based on the WMC vs GES results (68% vs 48%) (P < 0.0001). Ordering of additional test(s) was eliminated more often with WMC vs GES (71% vs 31%) (P < 0.0001). Prokinetics (P = 0.0007) and laxatives (P < 0.0001) were recommended more often based on the WMC vs GES results. Recommendations for prokinetics and gastroparesis diets were higher and neuromodulators lower in subjects with delayed emptying on both tests (all P ≤ 0.0006). Laxatives and additional motility tests were ordered more frequently for delayed compared with normal WMC colonic transit (P ≤ 0.02). Multiple motility tests were ordered more often on the basis of GES vs WMC findings (P ≤ 0.004). Antidumping diets and transit slowing medications were more commonly recommended for rapid WMC gastric emptying (P ≤ 0.03). WMC transit results promote medication changes and eliminate additional diagnostic testing more often than GES because of greater detection of delayed gastric emptying and profiling the entire gastrointestinal tract in patients with gastroparesis symptoms. Gastric scintigraphy and WMCs have differential impact on management decisions in suspected gastroparesis.


Local field effects in multicomponent media.
We investigate local-field effects in nonlinear optical materials composed of two species of atoms. One species of atom is assumed to be near resonance with an applied field and is modeled as a two-level system while the other species of atom is assumed to be in the linear regime. If the near dipole-dipole interaction between two-level atoms is negligible, the usual local-field enhancement of the field is obtained. For the case in which near-dipole-dipole interactions are significant due to a high density of two-level atoms, local-field effects associated with the presence of a optically linear material component lead to local-field enhancement of the near dipole-dipole interaction, intrinsic cooperative decays, and coherence exchange processes.


An evaluation of volume-based morphometry for prediction of mild cognitive impairment and Alzheimer's disease.
Voxel-based morphometry from conventional T1-weighted images has proved effective to quantify Alzheimer's disease (AD) related brain atrophy and to enable fairly accurate automated classification of AD patients, mild cognitive impaired patients (MCI) and elderly controls. Little is known, however, about the classification power of volume-based morphometry, where features of interest consist of a few brain structure volumes (e.g. hippocampi, lobes, ventricles) as opposed to hundreds of thousands of voxel-wise gray matter concentrations. In this work, we experimentally evaluate two distinct volume-based morphometry algorithms (FreeSurfer and an in-house algorithm called MorphoBox) for automatic disease classification on a standardized data set from the Alzheimer's Disease Neuroimaging Initiative. Results indicate that both algorithms achieve classification accuracy comparable to the conventional whole-brain voxel-based morphometry pipeline using SPM for AD vs elderly controls and MCI vs controls, and higher accuracy for classification of AD vs MCI and early vs late AD converters, thereby demonstrating the potential of volume-based morphometry to assist diagnosis of mild cognitive impairment and Alzheimer's disease.


The effect of strength training on muscle cellular stress in prostate cancer patients on ADT.
Androgen deprivation therapy (ADT) for prostate cancer (PCa) is associated with several side effects, including loss of muscle mass. Muscle atrophy is associated with reduced mitochondrial function and increased muscle cellular stress that may be counteracted by strength training. Thus, the aim of this study was to investigate the effect of strength training on mitochondrial proteins and indicators of muscle cellular stress in PCa patients on ADT. Men diagnosed with locally advanced PCa receiving ADT were randomised to a strength training group (STG) (n=16) or a control group (CG) (n=15) for 16 weeks. Muscle biopsies were collected pre- and post-intervention from the vastus lateralis muscle, and analysed for mitochondrial proteins (citrate synthase, cytochrome c oxidase subunit IV (COXIV), HSP60) and indicators of muscle cellular stress (heat shock protein (HSP) 70, alpha B-crystallin, HSP27, free ubiquitin, and total ubiquitinated proteins) using Western blot and ELISA. No significant intervention effects were observed in any of the mitochondrial proteins or indicators of muscle cellular stress. However, within-group analysis revealed that the level of HSP70 was reduced in the STG and a tendency towards a reduction in citrate synthase levels was observed in the CG. Levels of total ubiquitinated proteins were unchanged in both groups. Although reduced HSP70 levels indicated reduced muscle cellular stress in the STG, the lack of an intervention effect precluded any clear conclusions.


Construction of Genetic Linkage Maps in Multiparental Populations.
Construction of genetic linkage maps has become a routine step for mapping quantitative trait loci (QTL), particularly in animal and plant breeding populations. Many multiparental populations have recently been produced to increase genetic diversity and QTL mapping resolution. However, few software packages are available for map construction in these populations. In this paper, we build a general framework for the construction of genetic linkage maps from genotypic data in diploid populations, including bi- and multiparental populations, cross-pollinated (CP) populations, and breeding pedigrees. The framework is implemented as an automatic pipeline called magicMap, where the maximum multilocus likelihood approach utilizes genotypic information efficiently. We evaluate magicMap by extensive simulations and eight real datasets: one biparental, one CP, four multiparent advanced generation intercross (MAGIC), and two nested association mapping (NAM) populations, the number of markers ranging from a few hundred to tens of thousands. Not only is magicMap the only software capable of accommodating all of these designs, it is more accurate and robust to missing genotypes and genotyping errors than commonly used packages.


Improvement in out-of-hours outcomes following the implementation of Hospital at Night.
Hospital at Night (H@N) is a Department of Health (England) driven programme being widely implemented across UK. It aims to redefine how medical cover is provided in hospitals during the out-of-hours period. To investigate whether the implementation of H@N is associated with significant change in system or clinical outcomes. An observational study for 14 consecutive nights before, and 14 consecutive nights after the implementation of H@N. Data were collected from the Combined surgical and medical Assessment Unit (CAU), the 18 medical/surgical wards (The Ward Arc) and the four High Dependency Units (The Critical Care corridor) within the Royal Infirmary of Edinburgh. Following an overnight episode of clinical concern, data were gathered on response time, seniority of reviewing staff, patient outcome and the use of Standardized Early Warning Score (SEWS). Two hundred and nine episodes of clinical concern were recorded before the implementation of H@N and 216 episodes afterwards. There was no significant change in response time in the CAU, Ward Arc or Critical Care corridor. However, significant inter-speciality differences in response time were eradicated, particularly in the Critical Care corridor. Following the implementation of H@N, patients were reviewed more frequently by senior medical staff in CAU (28% vs. 4%, P < 0.05) and the Critical Care corridor (50% vs. 22%, P < 0.001). Finally there was a reduction in adverse outcome (defined as unplanned transfer to critical care/cardiac arrest) in the Ward Arc and CAU from 17% to 6% of patients reviewed overnight (P < 0.01). SEWS was more frequently and accurately recorded in CAU. This is the first study that we are aware of directly comparing out-of-hours performance before and after the implementation of H@N. Significant improvements in both patient and system outcomes were observed, with no adverse effects noted.


Phylogenetic analysis of the genus Chlamydia based on 16S rRNA gene sequences.
The phylogenetic relationships among Chlamydia spp. were investigated by comparing 16S rRNA gene sequences. In this analysis we used 14 strains of Chlamydia psittaci, including seven feline isolates, two avian isolates, two human isolates, one bovine isolates, one ovine isolate, and one koala isolate; and nine strains of Chlamydia trachomatis, including six human isolates, two swine isolates, and one mouse isolate. A phylogenetic analysis of the 16S rRNA gene sequences of these organisms and seven previously published sequences revealed eight genetic groups which formed two clusters. The first cluster was composed of C. pecorum, Chlamydia pneumoniae, and C. psittaci and included three genetic groups (one group containing avian, human, and ovine strains, one group containing feline strains, and one group containing guinea pig strains). The second cluster was composed of C. trachomatis and also included three genetic groups (one group containing human strains, one group containing swine isolates, and one group containing rodent strains). The strains in each genetic group exhibited similar genetic distances. The results of the phylogenetic analysis agreed with the results of previous genomic DNA, ompA gene allele, and biotyping studies. Therefore, the genetic groups based on genetic distances may be considered a criterion for species identification.


Niche tradeoffs, neutrality, and community structure: a stochastic theory of resource competition, invasion, and community assembly.
Stochastic niche theory resolves many of the differences between neutral theory and classical tradeoff-based niche theories of resource competition and community structure. In stochastic niche theory, invading species become established only if propagules can survive stochastic mortality while growing to maturity on the resources left unconsumed by established species. The theory makes three predictions about community structure. First, stochastic niche assembly creates communities in which species dominate approximately equally wide "slices" of the habitat's spatial heterogeneity. These niche widths generate realistic distributions of species relative abundances for which, contrary to neutral theory but consistent with numerous observations, there are strong correlations among species traits, species abundances, and environmental conditions. Second, slight decreases in resource levels are predicted to cause large decreases in the probability that a propagule would survive to be an adult. These decreases cause local diversity to be limited by the inhibitory effects of resource use by established species on the establishment (recruitment) of potential invaders. If resource pulses or disturbance allowed invaders to overcome this recruitment limitation, many more species could indefinitely coexist. Third, the low invasibility of high diversity communities is predicted to result not from diversity per se, but from the uniformly low levels of resources that occur in high-diversity communities created by stochastic competitive assembly. This prediction provides a potential solution to the invasion paradox, which is the tendency for highly diverse regions to be more heavily invaded.


Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.
The considerable therapeutic potential of human multipotent mesenchymal stromal cells (MSC) has generated markedly increasing interest in a wide variety of biomedical disciplines. However, investigators report studies of MSC using different methods of isolation and expansion, and different approaches to characterizing the cells. Thus it is increasingly difficult to compare and contrast study outcomes, which hinders progress in the field. To begin to address this issue, the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy proposes minimal criteria to define human MSC. First, MSC must be plastic-adherent when maintained in standard culture conditions. Second, MSC must express CD105, CD73 and CD90, and lack expression of CD45, CD34, CD14 or CD11b, CD79alpha or CD19 and HLA-DR surface molecules. Third, MSC must differentiate to osteoblasts, adipocytes and chondroblasts in vitro. While these criteria will probably require modification as new knowledge unfolds, we believe this minimal set of standard criteria will foster a more uniform characterization of MSC and facilitate the exchange of data among investigators.


A review of fundamental principles for animal models of DOHaD research: an Australian perspective.
Epidemiology formed the basis of 'the Barker hypothesis', the concept of 'developmental programming' and today's discipline of the Developmental Origins of Health and Disease (DOHaD). Animal experimentation provided proof of the underlying concepts, and continues to generate knowledge of underlying mechanisms. Interventions in humans, based on DOHaD principles, will be informed by experiments in animals. As knowledge in this discipline has accumulated, from studies of humans and other animals, the complexity of interactions between genome, environment and epigenetics, has been revealed. The vast nature of programming stimuli and breadth of effects is becoming known. As a result of our accumulating knowledge we now appreciate the impact of many variables that contribute to programmed outcomes. To guide further animal research in this field, the Australia and New Zealand DOHaD society (ANZ DOHaD) Animals Models of DOHaD Research Working Group convened at the 2nd Annual ANZ DOHaD Congress in Melbourne, Australia in April 2015. This review summarizes the contributions of animal research to the understanding of DOHaD, and makes recommendations for the design and conduct of animal experiments to maximize relevance, reproducibility and translation of knowledge into improving health and well-being.


Methyl-CpG binding protein MBD1 couples histone H3 methylation at lysine 9 by SETDB1 to DNA replication and chromatin assembly.
In mammals, heterochromatin is characterized by DNA methylation at CpG dinucleotides and methylation at lysine 9 of histone H3. It is currently unclear whether there is a coordinated transmission of these two epigenetic modifications through DNA replication. Here we show that the methyl-CpG binding protein MBD1 forms a stable complex with histone H3-K9 methylase SETDB1. Moreover, during DNA replication, MBD1 recruits SETDB1 to the large subunit of chromatin assembly factor CAF-1 to form an S phase-specific CAF-1/MBD1/SETDB1 complex that facilitates methylation of H3-K9 during replication-coupled chromatin assembly. In the absence of MBD1, H3-K9 methylation is lost at multiple genomic loci and results in activation of p53BP2 gene, normally repressed by MBD1 in HeLa cells. Our data suggest a model in which H3-K9 methylation by SETDB1 is dependent on MBD1 and is heritably maintained through DNA replication to support the formation of stable heterochromatin at methylated DNA.


A survey of physicians' knowledge and attitudes regarding antimicrobial resistance and antibiotic prescribing practices at the University Hospital of the West Indies.
To identify physicians' knowledge and attitudes regarding antimicrobial resistance and antibiotic prescribing practices at the University Hospital of the West Indies (UHWI). A cross-sectional survey of physicians at the UHWI was conducted between September 2008 and April 2009 using a 28-item, self-administered questionnaire. Eligible physicians from several specialities were identified from departmental rotas. A total of 174 physicians completed the questionnaire, a response rate of 73%. Most physicians considered antibiotic resistance to be an extremely important global problem (55%) but less significant nationally (35%). Factors identified as important in producing resistance included widespread use of antibiotics (91%), inappropriate empiric choices (79%) and use of broad-spectrum agents (70%). Hand-washing was not considered to be important in reducing resistance. Useful interventions included access to current information on local resistance patterns (90%), institutional specific antibiotic guidelines (89%) and educational programmes (89%). Antibiotic cycling (40%) and restriction (35%) were regarded as less helpful. Knowledge of resistance-prone antibiotics and specific resistant organisms at the UHWI was poor, except for methicillin-resistant Staphylococcus aureus (MRSA). Empiric therapy for common infections was appropriate in most cases, and antibiotic choices were guided by availability of drugs (89%) and patient factors such as renal disease or allergy (80%). Only 45% of physicians would de-escalate to a narrow-spectrum antibiotic guided by a microbiology report, and consultants were more likely to de-escalate therapy than junior staff (p = 0.002). Although physicians were aware of the problem of resistance to antibiotics and the contributory factors, their practice did not reflect measures to reduce it. Continuing educational programmes and institution-specific antibiotic prescribing guidelines are needed.


Atrial natriuretic factor inhibits central angiotensin II pressor responses.
Intracerebroventricular (i.c.v.) administration of human atrial natriuretic factor (ANF), fragment 1-25, in the dose range 3 to 20 micrograms/kg did not alter resting arterial pressure or heart rate in rats anesthetized with chloralose/urethan (60:600 mg/kg i.p.), while angiotensin II (ANG II), 1 microgram/kg, produced a significant increase in arterial pressure after i.c.v. application. This pressor effect induced by ANG II was abolished by simultaneous administration of ANF (3 micrograms/kg i.c.v.). In isolated strips of rabbit aorta preconstricted with ANG II (10 nM), ANF caused a dose-dependent relaxation. In intact rats, the increase in blood pressure following intravenously administered ANG II (0.1 and 1 microgram/kg) was not altered by the highest dose of ANF (20 micrograms/kg) given intracerebroventricularly. These results suggest that atrial peptides may play an important role in the regulation of blood pressure by interacting with both the central and peripheral actions of ANG II. Inhibition of the central pressor action of angiotensin by ANF appears to be independent of any direct peripheral effect of the atrial peptides.


Microinfusion of bupropion inhibits putative GABAergic neuronal activity of the ventral tegmental area.
The most common interpretation for the mechanisms of antidepression is the increase of the brain monoamine levels such as dopamine (DA). The increase of DA can reduce depression but it can also decrease the monoamine release because of autoreceptor inhibition. Although bupropion can decrease the dopamine release, there is evidence about stimulatory effects of chronic application of bupropion on ventral tegmental area (VTA) neurons. In this study, the intra-VTA acute microinfusion of bupropion on putative VTA non-Dopaminergic (VTA-nonDA) neuronal firing rates was evaluated by a single neuron recording technique. Animals were divided into 7 groups (sham, and 6 bupropion-microinfused groups with 1, 10(-1), 10(-2), 10(-3), 10(-4), and 10(-5) mol, 1 µl/3 min, intra-VTA). A single neuron recording technique was done according to the stereotaxic coordination. After 10 min baseline recording, ACSF or bupropion was microinfused. The recording continued to recovery period in the treated groups. The prestimulus time (PST) and interspike interval (ISI) histograms were calculated for every single unit. The assessment of the drug effect was carried out by one-way analysis of variance (ANOVA) and Post-hoc test. 126 non-DA neurons were separated. Bupropion could inhibit 116 neurons and 11 neurons had no significant response. Maximum inhibition was 79.1% of baseline firing rate with 44.3 min duration. The inhibitory effect of bupropion was dose-dependent. The acute inhibitory effects of bupropion on VTA-nonDA neurons can explain the fast inhibitory effects of bupropion and other antidepressants on the VTA. These data can explain some side effects of antidepressants.


A smart ink for the assessment of low activity photocatalytic surfaces.
The azo dye, basic blue 66 (BB66) is used in a photocatalyst activity indicator ink (paii) to assess the activity of low activity photocatalytic surfaces, such as commercial photocatalytic tiles and silicone contaminated self-cleaning glass. The BB66 paii is shown to respond much faster than a previously reported, resazurin (Rz) based paii, i.e. the use of a BB66 paii on low activity self-cleaning tiles was found to be >6 times faster than the Rz paii. The BB66 paii is also shown to be effective at assessing the activity of piece of commercial self-cleaning glass contaminated with a coating of silicone, on which the Rz ink, in contrast, failed to show any significant change in colour over the same time period.


Indirect effect of guanine nucleotides on antagonist binding to A1 adenosine receptors: occupation of cryptic binding sites by endogenous vesicular adenosine.
Guanine nucleotides such as guanosine 5'-(3-O-thio)triphosphate (GTP gamma S) have been found to increase the binding of antagonists to adenosine A1 receptors. This response can be attributed either to a direct effect of GTP on receptors to increase antagonist affinity or to an indirect effect to decrease the affinity of receptors for a pool of endogenous adenosine that cannot be readily removed from membranes. In this study, adenosine content was measured in preparations of membranes and 3-[(3-cholamidopropyl)dimethylamino]-1-propanesulfonate (CHAPS)-solubilized receptors by a sensitive radioimmunoassay. In both preparations, pools of adenosine (2.5-10 pmol/mg of protein) were detected that were resistant to deamination by added adenosine deaminase (0.5-3 units/ml) unless membrane lipids were first dissolved in acetone. Electron microscopic examination of crude CHAPS-solubilized receptors revealed the existence of small vesicles (< 1 microns in diameter). Furthermore, most "solubilized" receptors were retained by a 0.1-microns filter. The effects of GTP gamma S were evaluated on the binding of an antagonist, 3-(4-amino-3-125I-phenethyl)-1-propyl-8-cyclopentylxanthine (125I-BW-A844U), to A1 receptors of bovine brain membranes, receptors solubilized in CHAPS (crude solubilized), or receptors partially co-purified with G proteins by agonist affinity chromatography (partially purified). GTP gamma S (10 microM) increased antagonist binding to membranes (20-50%) and crude CHAPS-solubilized receptors (> 200%) but increased binding to partially purified receptors by only 10-15%. GTP gamma S decreased agonist (125I-N6-aminobenzyladenosine) binding and increased antagonist Bmax, but did not significantly decrease (5%) the dissociation rate of the antagonist. Omission of Mg2+ mimicked the effects of GTP gamma S on agonist and antagonist binding and increased both the association and dissociation rates of 125I-BW-A844U. These data suggest that a Mg(2+)-dependent GTP gamma S-induced increase in antagonist binding to membranes and solubilized receptors is primarily due to unmasking of cryptic binding sites occupied by contaminating vesicular adenosine. These findings are consistent with the observation that adenosine receptor antagonists have been found to have little or no inverse agonist physiological effects in well oxygenated tissues.


Impact of comorbidity on lung cancer survival.
Lung cancer is associated with smoking and age, both of which are associated with comorbidity. We evaluated the impact of comorbidity on lung cancer survival. Data on 56 comorbidities were abstracted from the records of a cohort of 1,155 patients. Survival effects were evaluated with Cox regression (outcome crude death). The adjusted R(2) statistic was used to compare the survival variation explained by predictive variables. No comorbidity was observed in 11.7% of patients, while 54.3% had 3 or more (mean 2.97) comorbidities. In multivariate analysis, 19 comorbidities were associated with survival: HIV/AIDS, tuberculosis, previous metastatic cancer, thyroid/glandular diseases, electrolyte imbalance, anemia, other blood diseases, dementia, neurologic disease, congestive heart failure, COPD, asthma, pulmonary fibrosis, liver disease, gastrointestinal bleeding, renal disease, connective tissue disease, osteoporosis and peripheral vascular disease. Only the latter was protective. Some of the hazards of comorbidities were explained by more directly acting comorbidities and/or receipt of treatment. Stage explained 25.4% of the survival variation. In addition to stage, the 19 comorbidities explained 6.1%, treatments 9.2%, age 3.7% and histology 1.3%. Thirteen uncommon comorbidities (prevalence <6%) affected 21.2% of patients and explained 3.5% of the survival variation. Comorbidity count and the Charlson index were significant predictors but explained only 2.5% and 2.0% of the survival variation, respectively. Comorbidity has a major impact on survival in early- and late-stage disease, and even infrequent deleterious comorbidities are important collectively. Comorbidity count and the Charlson index failed to capture much information. Clinical practice and trials need to consider the effect of comorbidity in lung cancer patients.


Hepatitis B virus reverse transcriptase sequence variant database for sequence analysis and mutation discovery.
Drug resistance resulting from reverse transcriptase (RT) mutations is one of the main obstacles to successful hepatitis B virus (HBV) therapy. Indeed, HBV treatment guidelines recommend HBV genotypic resistance testing for patients receiving nucleos(t)ide RT inhibitors (N(t)RTIs) who develop virological failure. N(t)RTI-resistance mutations at 10 RT positions have been well characterized in phenotypic studies, however, data are lacking on the relative frequency of these mutations in N(t)RTI-treated and untreated individuals. There are also few published data on the extent of amino acid variation at most of the 344 positions of HBV RT and the extent to which this variation is influenced by N(t)RTI treatment. We retrieved 23,871 HBV RT sequences from GenBank and reviewed the published reports of these sequences to ascertain the number of individuals from whom the sequences were obtained, the N(t)RTI treatments of these individuals, and the year and region of virus sampling. We then used these data to populate a relational database we named HBVrtDB. As of July 2010, HBVrtDB contained 6811 sequences from 3869 individuals reported in 281 references. Among these 3869 individuals, 73% were N(t)RTI-naïve and 27% received one or more N(t)RTIs. Among the 10 well-characterized N(t)RTI-resistance mutations, L80I/V, V173L, L180M, A181T, T184S, S202G and M204I/V were significantly associated with treatment with lamivudine, an l-nucleoside analog, and A181S/T/V and N236T were significantly associated with treatment with adefovir, an acyclic nucleoside phosphonate. A similar analysis of ten additional less well-characterized resistance mutations demonstrated a significant association with N(t)RTI treatment for four of the mutations: L82M, S85A, A200V, and Q215S. We also created an interactive program, HBVseq, to enable users to identify mutations in submitted sequences and retrieve the prevalence of these mutations in HBVrtDB according to genotype and N(t)RTI treatment. HBVrtDB and HBVseq are available at http://hivdb.stanford.edu/HBV/releaseNotes/.


Long-term epigenetic therapy with oral zebularine has minimal side effects and prevents intestinal tumors in mice.
Recent successes in the application of epigenetic drugs for the treatment of myelodysplastic syndrome have raised questions on the safety of long-term administration of DNA methylation inhibitors. We treated preweaned cancer prone Apc(Min/+) (Min) mice continuously with the DNA methylation inhibitor zebularine in their drinking water to determine the effects of the drug on normal mouse development as well as cancer prevention. Zebularine caused a tissue-specific reduction in DNA methylation at B1 short interspersed nucleotide elements in the small and large intestines of female Min mice but not in other organs examined after chronic oral treatment. No significant difference in the average weights of mice was observed during the treatment. In addition, analysis of global gene expression of colonic epithelial cells from the females indicated that only 3% to 6% of the genes were affected in their expression. We did not detect toxicity and abnormalities from the histopathologic analysis of liver and intestinal tissues. Lastly, we tested whether prevention of tumorigenesis can be achieved with chronic oral administration of zebularine in Min mice. The average number of polyps in Min females decreased from 58 to 1, whereas the average polyp number remained unaffected in Min males possibly due to differential activity of aldehyde oxidase. Taken together, our results show for the first time that long-term oral administration of zebularine causes a gender-specific abrogation of intestinal tumors while causing a tissue-specific DNA demethylation. Importantly, prolonged treatment of mice with epigenetic drugs resulted in only minor developmental and histologic changes.


THz-driven nonlinear intersubband dynamics in quantum wells.
In this work, we demonstrate the direct observation of non-equilibrium intersubband dynamics in a modulation-doped multiple quantum well sample induced by intense terahertz pulses. The transmission spectra show a clear dependence on the incident THz field strength, which gives rise to a multitude of nonlinear optical effects that go beyond the standard textbook two-level description of light-matter interaction. Of special interest is thereby the multiple octave spanning bandwidth of the used single-cycle THz pulses, which allows the phase-locked coupling of adjacent intersubband transitions. Examples of this interaction include the efficient, coherent population transfer, the THz induced undressing of collective excitations, and the THz Stark effect.


Activation of STIM1-Orai1 involves an intramolecular switching mechanism.
Stromal interaction molecule 1 (STIM1) stimulates calcium ion (Ca(2+)) entry through plasma membrane Orai1 channels in response to decreased Ca(2+) concentrations in the endoplasmic reticulum lumen. We identified an acidic motif within the STIM1 coiled-coil region that keeps its Ca(2+) activation domain [Ca(2+) release-activated Ca(2+) (CRAC) activation domain/STIM1-Orai activating region (CAD/SOAR)]-a cytoplasmic region required for its activation of Orai1-inactive. The sequence of the STIM1 acidic motif shows substantial similarity to that of the carboxyl-terminal coiled-coil segment of Orai1, which is the postulated site of interaction with STIM1. Mutations within this acidic region rendered STIM1 constitutively active, whereas mutations within a short basic segment of CAD/SOAR prevented Orai1 activation. We propose that the CAD/SOAR domain is released from an intramolecular clamp during STIM1 activation, allowing the basic segment to activate Orai1 channels. This evolutionarily conserved mechanism of STIM1 activation resembles the regulation of protein kinases by intramolecular silencing through pseudosubstrate binding.